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VDJtargeting SIGNED

Engineering T cells and B cells for Immunotherapy using V(D)J recombination

Total Cost €

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EC-Contrib. €

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Partnership

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 VDJtargeting project word cloud

Explore the words cloud of the VDJtargeting project. It provides you a very rough idea of what is the project "VDJtargeting" about.

engineering    region    shown    recombination    na    memory    mainly    class    antigen    engineer    integration    ve    ameliorate    recognition    efficacy    iuml    endogenous    antibody    autoimmune    affinity    secreted    safe    adeno    injected    oncogenic    promoterless    rare    subjected    exclusion    manipulations    facilitated    locus    differentiated       somatic    haematological    receptor    cancers    lack    vivo    desired    rss    car    signal    utilizing    reduces    express    expression    risk    cell    ex    clinical    maturation    secret    lymphocytes    aav    tcr    efficient    antigenic    disease    date    inserted    gene    diseases    therapeutic    auto    chimeric    reliance    engineered    adverse    implanted    potent    inducibly    loci    autoimmunity    escape    scaling    genes    activating    vectors    sequences    spurious    coding    expressing    expressed    immunotherapy    constant    rag    previously    models    hypermutation    diminished    flanked    accompanied    genetic    allelic    ab    integrate    negative    switching    promoter    reducing    cells    chains    proliferation    vdj    mice    incorporate    cancer    retention    activation    off    immune   

Project "VDJtargeting" data sheet

The following table provides information about the project.

Coordinator
TEL AVIV UNIVERSITY 

Organization address
address: RAMAT AVIV
city: TEL AVIV
postcode: 69978
website: http://www.tau.ac.il/

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Israel [IL]
 Total cost 1˙496˙875 €
 EC max contribution 1˙496˙875 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2017-STG
 Funding Scheme ERC-STG
 Starting year 2017
 Duration (year-month-day) from 2017-10-01   to  2022-09-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    TEL AVIV UNIVERSITY IL (TEL AVIV) coordinator 1˙496˙875.00

Map

 Project objective

T cell engineering has shown clinical success mainly in haematological cancers, but scaling up is challenging due to reliance on ex vivo manipulations. In addition, B cell engineering has not shown therapeutic efficacy to date. Here, we propose a novel immunotherapy approach, allowing safe and efficient engineering of B cells and T cells, both ex vivo and in vivo. We will use adeno associated vectors (AAV) to integrate chimeric antigen receptor (CAR) or T cell receptor (TCR) genes into loci coding TCR chains and to integrate antibody (Ab) genes into loci coding Ab chains. Previously, we used AAV facilitated gene targeting in vivo to ameliorate genetic diseases in mice. For lymphocytes we develop “VDJ targeting”: A promoterless receptor/Ab gene flanked by recognition signal sequences (RSS) will be inserted into the endogenous locus by the recombination activating gene (RAG) complex during V(D)J recombination. Only developing lymphocytes, expressing RAG, will incorporate the receptor/Ab gene, which will thus be expressed in potent naïve cells from the strong endogenous promoter. Targeted developing cells are subjected to negative selection, thus reducing risk of adverse autoimmunity. Lack of promoter reduces spurious expression and oncogenic risk upon rare off-target integration. Targeting endogenous loci may allow allelic exclusion. In B cells it may allow utilizing the endogenous constant region to express a B cell receptor and, upon activation, a secreted Ab. Activation may be accompanied by proliferation and affinity maturation, including somatic hypermutation and class switching, to allow a potent immune response, memory retention and diminished antigenic escape. Where controlled autoimmunity is desired, we will engineer B cells to inducibly secret an auto-Ab. We will demonstrate efficacy in cancer and autoimmune disease models implanted with lymphocytes that we engineered while ex vivo differentiated and in mice injected with vectors for in vivo VDJ targeting.

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